JP6630310B2 - Compositions for treating skin conditions comprising diindolylmethane and retinoids - Google Patents

Description

  The present application relates to a pharmaceutical composition or kit comprising a diindolylmethane (DIM) compound for use in the treatment of a skin condition such as acne. The composition comprises additional components in addition to the DIM to enhance the pharmaceutical effect of the DIM.

  DIM compounds have long been known as pharmaceutically active agents. In particular, naturally occurring DIM has been shown to be useful in treating human papillomavirus (HPV). U.S. Patent No. 6,059,064 discloses the use of DIM in the treatment of warts and warts, a condition caused by HPV infection. DIM is employed alone or in combination with immunopotentiating steroids.

  DIM has been used to treat a variety of other diseases as well as certain other skin conditions. U.S. Patent No. 6,064,064 describes the use of DIM for the treatment of acne, alopecia, hirsutism, and even prostate cancer. It is particularly preferred to combine DIM with other antiandrogens such as bicalutamide, cyproterone, finasteride, dutasteride, ketoconazole, nilutamide, and spironolactone. Non-Patent Document 1 discloses that DIM can be used to treat tumors in mice. U.S. Patent No. 6,064,064 discloses that DIM may be useful for treating acne, rheumatoid arthritis and cancer. U.S. Patent No. 6,047,064 discloses the use of DIM to treat the aging phenomenon. U.S. Patent No. 6,064,064 also discloses that other additives such as vitamin B may be used to improve nutrition. However, there is still a need to improve the activity and effectiveness of DIM treatment, especially with regard to skin conditions.

  DIM has also found use in combination with vitamin A in the treatment of many additional diseases. For example, U.S. Patent No. 6,047,064 discloses the use of DIM in combination with vitamin A for the treatment of cancer. U.S. Patent No. 6,037,064 discloses the use of DIM and Vitamin A for treating eye diseases. U.S. Patent No. 6,037,064 discloses similar combinations for treating respiratory diseases. U.S. Patent No. 6,047,086 discloses another similar combination for treating human cytomegalovirus.

WO 2003/034992 pamphlet US Patent Application Publication No. 2005/0058600 Chinese Patent Application No. 10142816 International Publication No. 2009/103754 pamphlet WO 2005/088942 pamphlet WO 2007/096886 Pamphlet WO 2006/083458 pamphlet WO 2006/047716 pamphlet

Molecular Carcinogenesis (vol. 49, pages 672 to 683, 2010), Kim et al.

  The inventors have long been interested in improving the treatment of skin conditions and have been particularly interested in acne, inflammation and aging phenomena. As mentioned above, DIM has so far found use in the treatment of many conditions, but its use in the treatment of skin conditions, which is of interest to the present inventors, has not been as effective as desired. . However, in two forms of the present invention, we surprisingly find that DIM is remarkably effective in treating and preventing such skin conditions when combined with certain carefully selected synergistic ingredients. Has been found to have a significant effect. We are also interested in reducing the side effects of known treatments and have found that a surprising combination of each form of the invention improves the side effect profile compared to known treatments.

Accordingly, in a first aspect, the present invention provides a composition for use in the treatment of a skin condition,
(A) a first component comprising a substituted or unsubstituted diindolylmethane compound;
(B) a second component comprising a substituted or unsubstituted retinoid compound;
The composition characterized by containing is provided.

  We particularly surprisingly treat and prevent the effects of acne, inflammation and / or skin aging when DIM is combined with the selected synergistic second component. Has a remarkable effect.

  The present invention is a pharmaceutical kit for individual administration, simultaneous administration, or continuous administration for use in the treatment of a skin condition, comprising a first component and a second component, A pharmaceutical kit is further provided, wherein the component and the second component are as described above.

  Clinical trials have shown that compositions of the invention in the form of a composition or kit have significant advantages over known treatments. The results of the test are described in more detail in the examples.

The present invention will be described in detail, by way of example only, with reference to the following drawings.
FIG. 1 shows a patient with acne vulgaris from Group A before treatment with a composition of the invention containing BioResponse DIM (BioResponse DIM) and Vitamin A. FIG. 2 shows the patient from FIG. 1 after treatment with a composition of the invention comprising BioResponse DIM and Vitamin A. FIG. 3 shows a patient with acne vulgaris from Group B before treatment with a composition of the invention comprising BioResponse DIM and Vitamin A. FIG. 4 shows the patient from FIG. 3 after treatment with a composition of the invention comprising BioResponse DIM and Vitamin A.

  The components of the composition will be described in more detail.

  As mentioned above, the first component comprises a diindolylmethane (DIM) compound. The first component is not particularly limited provided it comprises a DIM compound, and may therefore also comprise one or more further DIM compounds of the type described below.

  The DIM compound may be any compound containing a diindolylmethane group, but is preferably a compound having the following structure.

Here, the R groups may be the same or different substituents. Examples of the substituent include, but are not particularly limited to, any organic group, and a B atom, Si atom, N atom, P atom, O atom, S atom, or halogen atom (eg, F, Cl, Br, or I). It may include at least any one or more atoms from any group of IIIA, IVA, VA, VIA or VIIA of the periodic table.

  When the substituent comprises an organic group, the organic group preferably comprises a hydrocarbon group. The hydrocarbon group may include a linear, branched or cyclic group. Independently, the hydrocarbon groups may include aliphatic or aromatic groups. Also, independently, the hydrocarbon group may include a saturated or unsaturated group.

  If the hydrocarbon contains an unsaturated group, it may include one or more alkene functional groups and / or one or more alkyne functional groups. If the hydrocarbon comprises a straight or branched chain group, it may comprise one or more primary, secondary and / or tertiary alkyl groups. Good. When the hydrocarbon contains a cyclic group, it may contain an aromatic ring, an aliphatic ring, a heterocyclic group, and / or a fused ring derivative of these groups. Cyclic groups are therefore not only benzene, naphthalene, anthracene, indene, fluorene, pyridine, quinoline, thiophene, benzothiophene, furan, benzofuran, pyrrole, indole, imidazole, thiazole, and oxazole groups, but also It may include regioisomers of the group.

  The carbon number of the hydrocarbon group is not particularly limited, but preferably, the hydrocarbon group contains 1 to 40 C atoms. The hydrocarbon group may therefore be a lower hydrocarbon (1 to 6 C atoms) or a higher hydrocarbon (7 C atoms or more, for example 7 to 40 C atoms). The number of atoms in the ring of the cyclic group is not particularly limited, but preferably the ring of the cyclic group contains 3 to 10 atoms such as 3, 4, 5, 6, or 7 atoms.

  In addition to the heteroatom-containing groups described above, any other group defined above may be a B, Si, N, P, O, S, or halogen atom (eg, F, Cl, It may include one or more atoms from any group of IIIA, IVA, VA, VIA or VIIA of the Periodic Table, such as Br or I). Accordingly, the substituents include hydroxy, carboxylic acid, ester, ether, aldehyde, ketone, amine, amide, imine, thiol, thioether, sulfate, sulfonic, and phosphoric acid groups. It may include any common functional group in one or more organic chemistry, such as a group. Substituents may also include derivatives of these groups, such as carboxylic anhydrides and carboxylic halides.

  In addition, optional substituents may include a combination of two or more substituents and / or functional groups as defined above.

Preferably, selection substituent is hydrogen, and _C 1 -C ₆ alkyl group (e.g., methyl group, an ethyl group, a propyl group, an isopropyl group, and butyl group) from _C 1 -C ₆ hydrocarbon substituents such as Is done. Most preferably, both R substituents are hydrogen atoms.

The indolyl groups in the above formula are not particularly limited, but may be the same or different. Preferably, they are both indol-3-yl groups, but alternatively they may both be indol-2-yl groups, or one is an indol-3-yl group and the other is an indol-2-yl group —It may be an yl group. The indolyl group may have the same or different substituents, all the substituents may be hydrogen atoms and may be unsubstituted, or may be substituted with one or more substituents as defined above. It may be. Preferably, selection substituent is hydrogen, and _C 1 -C ₆ alkyl group (e.g., methyl group, an ethyl group, a propyl group, an isopropyl group, and butyl group) from _C 1 -C ₆ hydrocarbon substituents such as Is done. Most preferably, all substituents are hydrogen atoms, ie, the indolyl group is unsubstituted.

  Typically, but not exclusively, the first component is a substituted or unsubstituted 3,3 ′ diindolylmethane compound and a substituted or unsubstituted 2,2 ′ selected from the structures: At least one of a diindolylmethane compound,

Here, the R groups may be the same or different and are selected from a hydrogen atom or a C ₁ -C ₆ hydrocarbon substituent.

  More preferably, the first component comprises at least one of a 3,3 'diindolyl methane compound and a 2,2' diindolyl methane compound selected from the following structures.

  As described above, the compositions and kits of the present invention include a second component that includes a substituted or unsubstituted retinoid compound. The second component typically has a beneficial effect that complements the effect of the first component, complements the effect of the first component, or both. In the context of the present application, the effect of the second component may therefore be complementary to the effect of the first component (ie, the effect is different from the effect of the first component, but the skin in question is May be additionally beneficial for the treatment of the condition) or supplement the effect of the first component (ie, it produces an additive effect or enhances the medicinal effect of the first component, It may have the same effect as the first component). Components having a synergistic effect with the first component or any other beneficial relationship are therefore intended to be encompassed by this definition.

  The composition may also include one or more additional components. The additional components are not particularly limited, but typically provide the beneficial effects described above. In some embodiments, the additional component is a further substituted or unsubstituted retinoid compound, an antibiotic compound, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulfur, a sulfur-containing compound, a substituted or unsubstituted compound. Selected from one or more of a salicylic acid compound, a substituted or unsubstituted resorcinol compound, a plant product, a mineral, a vitamin (typically not a vitamin A which may alternatively be present as a retinoid compound), and a nutritional supplement product. .

  Further components may include one of the compounds as described above, or any of two or more of these compounds, depending on the requirements of the formulation.

  The retinoid compound of the second component may be, without limitation, any compound known in the art that is suitable for use on the skin. For example, it may be selected from substituted or unsubstituted first generation retinoids, substituted or unsubstituted second generation retinoids, and substituted or unsubstituted third generation retinoids. More preferably, the retinoid is a substituted or unsubstituted first generation retinoid. Typically, first generation retinoids are substituted or unsubstituted retinol, substituted or unsubstituted retinal, substituted or unsubstituted tretinoin (eg, retinoic acid or retin A), substituted or unsubstituted isotretinoin (eg, , Accutane®), and substituted or unsubstituted alitretinoin. Most preferably, the retinoid contains vitamin A. When the retinoid is a second generation retinoid, the retinoid is typically selected from substituted or unsubstituted etretinate, and substituted or unsubstituted acitretin. When the retinoid is a third generation retinoid, the retinoid is typically selected from substituted or unsubstituted tazarotene, substituted or unsubstituted bexarotene, and substituted or unsubstituted adapalene.

  If the further component comprises an antibiotic compound, the antibiotic compound may be, without limitation, any compound known in the art suitable for use on the skin. Typically, the antibiotic compound is suitable for oral and / or topical administration and is selected from tetracycline, oxytetracycline, minocycline, doxycycline, erythromycin, and trimethoprim.

  If the further component comprises an azelaic acid compound, the azelaic acid compound may be, without limitation, any compound known in the art suitable for use on the skin. Typically, azelaic acid compounds have antimicrobial and / or anti-inflammatory properties.

  If the further component comprises an oral contraceptive compound, the oral contraceptive compound may be, without limitation, any compound known in the art suitable for use on the skin. Typically, oral contraceptives include female hormones and / or compounds with female hormone activity that can counteract the effects of male hormones. In some embodiments, the female hormone is estrogen and the male hormone is testosterone.

  If the further component comprises sulfur or a sulfur-containing compound, the sulfur or sulfur-containing compound may be, without limitation, any compound known in the art suitable for use on the skin. Typically, the sulfur or sulfur-containing compound comprises sulfur, alone or in combination with other substances such as alcohols, salicylic acids, and / or resorcinols.

  If the further component comprises a resorcinol compound, the resorcinol compound may be, without limitation, any compound known in the art suitable for use on the skin. Typically, resorcinol compounds have antimicrobial and / or anti-inflammatory properties.

Where the additional ingredient comprises a plant product, it typically, but not exclusively, comprises an extract from one or more of the following:
-Nettle (nettle)-has significant anti-inflammatory effects to help reduce redness and swelling in acne-Black currant (blackcurrant)-has significant anti-inflammatory and anti-oxidative effects-Echinacea and Echinacea angustifolia At least one of the following: containing an active substance that enhances the activity of the immune system and reduces the inflammatory and antioxidant effects Jashou-acts via its antibacterial, antifungal and astringent properties Verberis aquifolie Umm (Oregon grape)-can reduce sebum production and reduce infections and inflammation. Chamomile Matricaria (German chamomile)-has antibacterial properties and inactivates bacterial toxins. Can reduce inflammation and accelerate wound healing. ・ Portrait of pokeweed (poke root)
Cruciferous vegetables-a synergistic effect can be achieved by the addition of extracts, concentrates and processed extracts of cruciferous vegetables such as broccoli and brussels sprouts. These can provide active products with significant additional antioxidant and anti-inflammatory effects.

Where the further ingredient comprises a mineral, it typically, but not exclusively, comprises one or more of the following:
Zinc-can help reduce inflammation and healing of damaged skin.It can help promote the body's ability to degrade chromium-glucose.Helps maintain and maintain a balance of reduced levels of selenium-antioxidant enzymes. Can reduce sexual acne and help reduce the appearance of scars

Where the further ingredient comprises a vitamin, it typically, but not exclusively, comprises one or more of the following:
Vitamin B complex-a combination of vitamin B (Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B4, Vitamin B5, Vitamin B6, Vitamin B7, Vitamin B9 and Vitamin B12)-a hormone that plays an important role in acne symptoms Vitamin C-a highly effective antioxidant that stimulates tissue growth and repair. Vitamin E-a powerful antioxidant that can contribute to the healing process of acne

If the further ingredient comprises a further nutritional supplement product, it comprises a product having some further nutritional or pharmaceutical properties that complement or supplement the effects of the first and / or second ingredient. . Typically, but not exclusively, additional nutritional supplement products may be selected from one or more of the following.
Evening primrose oil-contains fatty acids that can help reduce inflammation associated with skin symptoms-Plant isoflavones-Food derived from soy and red clover-Has important natural antioxidant properties and estrogen hormone balancing Turmeric-has anti-inflammatory properties derived from curcumin, the main active ingredient-omega-3 oil-long chain n-3 fatty acids may have anti-inflammatory activity

The compound of the second component (and / or the additional component) may be substituted or unsubstituted. If the compounds are substituted, they may be substituted with any of the substituents defined above. Preferably, selection substituent is hydrogen, and _C 1 -C ₆ alkyl group (e.g., methyl group, an ethyl group, a propyl group, an isopropyl group, and butyl group) from _C 1 -C ₆ hydrocarbon substituents such as Is done. Most preferably, all substituents are hydrogen atoms, ie the compounds are unsubstituted.

  A particularly advantageous embodiment of the present invention is a composition wherein the first component comprises unsubstituted 3,3'diindolylmethane and the second component comprises a vitamin A compound (eg, vitamin A palmitate) or It is a kit. Further advantageous additives and excipient compounds for inclusion in such advantageous embodiments are one or more of vitamin E, vitamin C, phosphatidylcholine, microcrystalline cellulose (vegetable fiber), magnesium stearate and silica. (Further descriptions of additives and excipients are provided below).

  Skin conditions for which the compositions and kits of the invention may be used for treatment are not particularly limited, but typically include acne, dermatitis, and (such as wrinkles and other age-related wounds). Selected from skin aging effects. In a more preferred embodiment of the invention, the acne comprises acne vulgaris, seborrhea, comedones, papules, pustules, nodules, cysts, coughs and scarring.

  The use of the formulation of the composition (and the components of the kit) in the present invention is not particularly limited, and any formulation suitable for administration to humans or other subjects may be used. However, typically, the compositions (and components of the kit) are formulated for oral or topical administration. Thus, the compositions (and components of the kit) may be provided in the form of tablets, capsules, gels, creams or ointments.

  Further description describes the bioavailability of the DIM component. Diindolylmethane (DIM) is a natural compound formed during the autolysis of glucobrassin, which is present in edible plants of the genus Brassica such as broccoli, cabbage, brussels sprouts, cauliflower, and kale. Autolysis of glucobrassin requires a catalytic reaction of the enzyme myrosinase, which is endogenous to these plants and is released upon cell wall rupture. The compounds are usually produced by chemical synthesis, but may be prepared by natural means from extracts of the Brassica veggies described above, in particular from germinated broccoli, or from broccoli seeds. As noted above, any DIM compound or combination of DIM compounds may be employed in the present invention. Therefore, as described above, the DIM compound may be a synthetic product, or may be a natural product obtained from a Brassica plant.

  Typically, however, the diindolylmethane compound has been modified to increase the required bioavailability in order to reduce the required dosage. One useful DIM with increased bioavailability is BioResponse Diindolylmethane (from BioResponse LLC).

  The dose of the DIM component is not particularly limited, provided that it is sufficiently low to avoid toxicity while maintaining the required pharmaceutical effect. The dosage may depend on the bioavailability of the DIM, but will depend on whether it is a natural or synthetic product and whether it is adapted to improve bioavailability. Can change. Typically, the first component is in a form suitable to provide a daily DIM dose of 500 mg or less, preferably 10 mg to 500 mg. Most preferably, it is about 150 mg or about 350 mg. For DIMs that are not adapted to improve bioavailability, higher doses are preferred. More preferably, the first component is in a form suitable to provide a daily DIM dose of 15 mg to 100 mg, preferably 18 mg to 75 mg. For DIMs that are adapted to improve bioavailability, lower dosages are preferred.

  The dosage of the substituted or unsubstituted retinoid compound component is not particularly limited, provided that it is sufficiently low to avoid toxicity while maintaining the required pharmaceutical effect. The dosage may depend on the bioavailability of the retinoid compound, but will depend on whether it is a natural or synthetic product and whether it is adapted to improve bioavailability. Can change. Typically, the second component has a daily dose of 5,000 μg or less, preferably 3,000 μg or less, preferably 50 μg or more, 100 μg or more, or 200 μg or more, more preferably 200 μg to 3,000 μg. It is a form suitable for providing.

  In a more typical embodiment, the daily dosage is provided in the form of one or more capsules or tablets, preferably in the form of two or four capsules or tablets. In these embodiments, the capsules or tablets are simultaneously inoculated with two tablets, for example, one in the morning and one at night, or four evenly distributed over the course of the day, or twice a day. It is designed to be.

  At least one of the first component and the second component in the composition and the kit may include at least one of one or more additional additives, excipients, and adjuvants. These additives, excipients, and adjuvants may increase their effectiveness of the first component and / or the second component or form a working formulation of the drug. It is not particularly limited, provided that it is advantageous to. Diindolylmethane is a lipophilic oil-soluble compound. The presence of oils and other lipophilic compounds such as phosphatidylcholine and vitamin E, as well as other oil-soluble phytochemicals, greatly increase the absorption and bioavailability of DIM upon oral administration. Thus, the first component typically includes vitamin E and / or one or more additional oil-soluble and / or lipophilic compounds such as phosphatidylcholine. Further advantageous additives may be added to the first component and / or the second component. These include, but are not limited to, microcrystalline cellulose (vegetable fiber), magnesium stearate, and silica.

  The present invention further provides a method for preparing the composition of the present invention. The method is not particularly limited, and any method known in the art for blending or mixing such components, especially blending or mixing powders. A method may be adopted. Thus, the method includes mixing a first component with a second component to form the composition. In some embodiments, the first component and the second component are each separately mixed with one or more excipients and / or additives before being mixed together to form a composition. In other embodiments, the components, additives, and / or excipients may be added continuously to the mixture during the mixing step.

  The choice of excipients and method of mixing may be adapted to overcome any mixing, flow and filling problems, or imprinting problems of the composition. The bioresponse DIM is provided in a microencapsulated form such that the powder particles have a tendency to agglomerate with each other. In such a situation, the mixing method is adapted so as not to create hot spots of increased concentration of the active ingredient. In addition, the composition is hydrous and light sensitive so that the number of treatments / mixings is kept to a minimum and the powder is protected from both light and air in the reservoir.

  As additives and excipients, microcrystalline cellulose, magnesium silicate, tricalcium phosphate and magnesium stearate (conventional lubricants) are preferred to aid in flow characteristics and / or lubrication. However, if desired, other additives and excipients known in the art may be used. In some embodiments, the composition desirably comprises 55% to 60% by weight of tricalcium phosphate.

  Accurate mixing of all ingredients is important to achieve a uniform capsule filling of the active ingredient. V-blender is very effective for good mixing. Preferably, a minimum 316 grade stainless steel container is used for this step. The sieving is preferably performed at one or more of the beginning, middle, and end of the process. In order to validate the method and formulation, it is necessary to complete a blending survey to confirm blend uniformity. Such methods and techniques are known in the art.

The present invention also provides a composition for use in treating a skin condition, comprising:
(A) a first component comprising a substituted or unsubstituted diindolylmethane compound;
(B) a second component different from the first component, having a beneficial effect that complements the effect of the first component and / or complements the effect of the first component; A second component characterized by:
Wherein the second component is an antibiotic compound, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulfur, a sulfur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound , A second form comprising a composition selected from plant products, minerals, vitamins, and dietary supplements.

  In this second form, an antibiotic compound, a substituted or unsubstituted azelaic acid compound, an oral contraceptive compound, sulfur, a sulfur-containing compound, a substituted or unsubstituted salicylic acid compound, a substituted or unsubstituted resorcinol compound, a plant product , Minerals, vitamins, and nutritional supplement products may be any compound or product as described above in connection with the additional ingredients used in the first aspect of the invention. Thus, in a second aspect of the invention, the second component is not a retinoid compound, but is instead selected from the compounds described above.

  Any of the preferred features described in the claims and specification in relation to the first aspect of the invention may be applied to the second aspect of the invention. The methods, uses and kits of the first aspect are also applicable to the second aspect.

  The invention will be described in more detail, by way of example only, with reference to the following specific embodiments.

Composition Preparation Two different batches of the DIM and Vitamin A formulations were prepared. Details of the manufacture and formulation are described below.

Formulation 1
One capsule contains:
-75 mg of DIM (BioResponse LLC)
200 μg of vitamin A retinol palmitate equivalent (366.4 μg of retinyl palmitate). This corresponds to 2.666 mg of 250,000 IU / g Vitamin A palmitate (BASF).
175 mg of tricalcium phosphate 20 mg of microcrystalline cellulose 10 mg of vitamin C (ascorbic acid)
-10 mg of fumed silicon dioxide (or finely particulate precipitated silica)
・ 6mg magnesium stearate

Mixing Method of Formulation 1 Mixing was performed in an order process according to the following protocol.
1. The DIM was sieved through a fine sieve and then mixed with magnesium stearate and half of tricalcium phosphate and silicon dioxide in a V mixer for 10 minutes.
2. Separately, vitamin C and retinyl palmitate were mixed with a second half of tricalcium phosphate and microcrystalline cellulose in a V mixer for 10 minutes.
The mixed powders obtained from 3.1 and 2 were mixed together in a V-mixer for 20 minutes, then sieved and further mixed in a V-mixer for 1 hour and 10 minutes.
4. The mixed powder was transferred to a suitable opaque hermetic container to keep light and oxygen contact to a minimum.
5. Samples were taken from the top and bottom of the batch to check for mixing uniformity.

Formulation 2
One capsule (297 mg) contains:
-75 mg of DIM (BioResponse LLC)
200 μg of vitamin A retinol palmitate equivalent (366.4 μg of retinyl palmitate). This corresponds to 1.333 mg of 500,000 IU / g vitamin A palmitate (BASF).
・ 175mg tricalcium phosphate ・ 20mg cellulose fiber ・ 10mg vitamin C (ascorbic acid)
-10 mg of silicon dioxide (Neosyl)
・ 6mg magnesium stearate

Mixing method of preparation 2 The DIM was sieved well through a fine mesh and passed through a clean sterile plastic bag. The sieved DIM, vitamin C, and retinyl palmitate were first premixed for 5 minutes in a sealed plastic bag with silicon dioxide.
2. The tricalcium phosphate and microcrystalline cellulose were then added to the premix and mixed well for another 5 minutes. The resulting mixture was added to a V mixer and mixed for 10 minutes.
3. Magnesium stearate was then added and the powder was mixed for another 10 minutes.
4. The resulting mixed powder was removed and passed through a fine grade sieve. This was then returned to the V mixer and mixed for 30 minutes.
5. The resulting mixture was transferred to a suitable opaque hermetic container to minimize light and oxygen exposure.
6. Samples were taken from the top, center and bottom of the batch to check the uniformity of mixing.

Encapsulation The formulations mentioned above may be encapsulated. The DIM was spray-dried into particles approximately 8 μm to 12 μm in diameter. Powder flowability of particles of this size is very challenging. Due to the particular ingredients used to achieve bioavailability requirements, the powder is slightly sticky. For this reason, certain types of encapsulation devices may have the difficulty of continuous operation without stopping the cleaning of the punch face or the adjustment of the filling dose.

  DIM is known to be light sensitive. Thus, opaque capsules, typically size "0" capsules, are preferred. Lightfast containers are preferred.

Patient Study The purpose of this study was to confirm the effectiveness of using oral DIM with vitamin A to treat grade II to Great IV active acne. The results showed a remarkable symptom improvement over a period of 3 months without side effects or worsening of the symptoms.

  The survey was performed using two test groups, Group A and Group B. The composition employed comprised Bioresponse DIM (75 mg per capsule) along with Solgar Vitamin A (retinyl palmitate) (5,000 IU per tablet).

Group A received 150-300 mg DIM with 5,000-10,000 IU vitamin A daily. The results were analyzed using:
-Visia skin analyzer-Photo-Self-report: Group A evaluated its own acne before starting supplementation and again at the end of the three months, on a scale of 1-10, 1 being good and 10 being bad. .
The results (evaluation on a scale of 10 out of 10) are shown in Table 1.

Group B received 300 mg DIM with 2,500 IU vitamin A daily. The results were analyzed using:
-Visia skin analyzer-Photo-Self-report: At the start of the test, subjects rated their acne on a scale of 1-10, with 1 being good and 10 being bad. Subjects were then asked to evaluate their skin again after one, two, and three months (end of the study).
Different rating scales were used. This time, subjects were asked to rate their own acne on a scale of 1-6, with 1 being their skin best and 6 being the worst. Table 2 shows the results (evaluation on a scale of 10 or 6 in percent).

result

Group A self-scoring

  The average performance of Group A before treatment was 67%, while the average performance after treatment was 29%, showing a very large improvement. Pictures showing the symptoms before and after the patient 12 in Group A are shown in FIGS. 1 and 2, respectively.

Group B self-scoring

  The average performance of Group B before treatment was 69%, while the average performance after treatment was 46%, again showing a very large improvement. Pictures showing the symptoms before and after the patient 11 of the group B are shown in FIGS. 3 and 4, respectively.

  The results showed that 18 of the 23 patients who completed the study showed improvement in symptoms (Patient A7, Patient B1, Patient B4, Patient B9, and Patient B10 did not show major changes in symptoms). The average of the 18 people was a 41% decrease, which represents a 59% improvement in the original performance.

  Evidence for the typical reduction in acne exhibited by patients treated with the agents of the present invention is provided in FIGS. 1-4 in "before and after" form. Significant improvement is clearly visible.

  These results demonstrate the great potential of the proposed combination formulation in treating acne and related conditions, especially when DIM with improved bioavailability (compared to pure DIM) is employed. Shows sex.

Claims (17)

(A) a 3,3′-diindolylmethane compound having the following structure:

A first component comprising:
(B) a second component comprising retinyl palmitate for use in the treatment of acne, skin inflammation or skin aging,
A composition wherein the ratio of the first component to the second component (mg: μg) is between 10: 3000 and 500: 200.   The composition according to claim 1, wherein the ratio is between 150: 3000 and 500: 200.   3. The composition according to claim 2, wherein the ratio is between 15: 3000 and 100: 200.   The composition according to claim 3, wherein the ratio is between 18: 3000 and 75: 200. (A) a 3,3′-diindolylmethane compound having the following structure:

A first component comprising:
(B) a second component comprising retinyl palmitate for use in the treatment of acne, skin inflammation or skin aging,
A composition wherein the ratio of the first component to the second component (mg: IU) is between 150: 10,000 and 300: 5,000.   The composition of claim 5, wherein the ratio of the first component to the second component (mg: IU) is about 300: 2,500.   The composition is selected from a retinoid compound, an antibiotic compound, an azelaic acid compound, an oral contraceptive compound, sulfur, a sulfur-containing compound, a salicylic acid compound, a resorcinol compound, a plant product, a mineral, a vitamin, and a nutritional supplement product. The composition according to any one of claims 1 to 6, further comprising a third component. The antibiotic compound is suitable for oral or topical administration, and is selected from tetracycline, oxytetracycline, minocycline, doxycycline, erythromycin, and trimethoprim;
The azelaic acid compound has antibacterial and / or anti-inflammatory properties,
The oral contraceptive comprises a female hormone, or a compound having a female hormone activity capable of counteracting the effect of a male hormone,
The female hormone is estrogen,
The male hormone is testosterone,
The resorcinol compound has antibacterial or anti-inflammatory properties,
The composition of claim 7, wherein the substituted compound comprises one or more C1-C6 hydrocarbon substituents.   The composition according to any one of claims 1 to 8, wherein the first component is a natural product obtained from a Brassica plant.   The composition according to any one of claims 1 to 9, wherein the first component further comprises one or more lipophilic compounds selected from vitamin E and phosphatidylcholine.   The composition according to any one of claims 1 to 10, wherein the composition further comprises at least one of an excipient and an adjuvant.   12. The composition according to any one of claims 1 to 11, wherein the composition is formulated for oral or topical administration.   13. The composition according to claim 12, wherein said composition is in the form of a tablet, capsule, gel, cream or ointment. The first component provides a daily dosage of 10 mg to 500 mg of diindolylmethane, and the second component provides a daily dosage of 200 μg to 3,000 μg of retinyl palmitate. The composition according to any one of claims 1 to 13, characterized in that: The composition according to claim 14, characterized in that the daily dose of diindolylmethane and the daily dose of retinyl palmitate are provided in the form of two or four capsules or tablets. .   16. A method of preparing a composition for use in treating acne according to any one of the preceding claims, wherein the first component is mixed with the second component. A method comprising forming an object.   The first component and the second component are each separately mixed with one or more excipients and / or additives before being mixed together to form the composition. 17. The method of claim 16, wherein